Migraine headache afflicts 20% of the population and causes major economic losses. Despite its high prevalence and serious economic consequences, its physiological, metabolic and molecular basis remains poorly understood and under-investigated. This application represents a joint effort by basic and clinical neuroscientists to understand the biological basis of migraine headache. Aiming to achieve a greater understanding of the neural substrate of migraine aura and headache, our program comprises 3 multidisciplinary Projects, plus a Scientific and an Administrative Core. Project 1 proposes to examine cortical spreading depression (CSD) in rats and in genetically modified mice carrying the R192Q missense mutation in P/Q-type Ca+* channels found in familial hemiplegic migraine. We will expand upon a recent novel finding that prophylactic antimigraine drugs suppress the susceptibility to CSD. Suppression of CSD is the first identified coherent physiological action for these pharmacologically distinct drugs, and emphasizes the importance of CSD to migraine pathophysiology. Project 1 will also expand upon our recent preliminary findings that thresholds for CSD become reduced during estrogen withdrawal as a mechanism to explain enhanced susceptibility in females to migraine headaches during menses. Project 2 will determine whether CSD is capable of activating meningeal nociceptors and central trigeminovascular neurons, and whether such activation depends upon the activation and degranulation of local mast cell or mediated by local activation of parasympathetic fibers originating in the sphenopalatine ganglion. Project 3 will examine the similarities and differences between patients with migraine (with and without aura), and test the hypothesis that CSD is the pathophysiological mechanism underlying both types of migraine. It will study the role of the cerebellum in migraine, and will build on preliminary findings showing long-term anatomical changes in the cortex and white matter of migraineurs to address the question: Is migraine a progressive disease? Taken together our 3 projects are mechanistically driven, multi-disciplinary, clinically relevant, molecular in orientation, and incorporate state of the art imaging.